Considerable effort over the years has been devoted to discovering and improving analytical techniques for measuring biological substances in connection with medical and industrial applications. An example of one such technique developed concerned polarographic electrode systems which wer used to measure various biological materials qualitatively and quantitatively, and reference is made to my earlier U.S. Pat. No. 2,913,386 describing such a polarographic electrode system for the measurement of oxygen and the like. Reference is also made to my U.S. Pat. No. 3,380,905 which pertains to an improvement of the polarographic electrode system described in the above-mentioned U.S. patent.
About twenty years ago, enzyme-coupled electrodes were reported for the polarographic analysis of biological substances. For example, in my U.S. Pat. Nos. 3,539,455 and 3,913,386, membrane polarographic electrode systems and methods were described for the rapid and accurate quantitative analysis of biological substances which theretofore could not be analyzed directly by polarographic methods. According to the description in my U.S. Pat. No. 3,539,455, small molecular substances, such as glucose, were measured with a membrane polarographic electrode system. By use of cellulose or another membrane which is permeable to small molecules, such as glucose, but is impermeable to proteins, the membrane kept glucose oxidase enzyme on the side of the membrane with the anode for reaction with glucose. Therefore, for example, if a sample of blood were placed on the membrane side opposite the electrode, with an aqueous solution of the enzyme and oxygen on the electrode side of the membrane, the low molecular weight materials, such as glucose, passed from the blood samples through the membrane for enzymatic reaction adjacent the electrode. After a certain period of time a steady state was reached when the hydrogen peroxide concentration was directly proportional to the glucose concentration and the cell produced a current flow as a function of the amount of hydrogen peroxide being formed which served as an indication of the amount of glucose present. As disclosed in my article entitled "Electrode Systems for Continuous Monitoring in Cardiovascular Surgery", N.Y. Acad. of Sciences. 102:29-45 (1962), the Clark oxygen electrode could be arranged so that it was sensitive to glucose by virtue of the fact that oxygen was consumed by enzymatic reaction in proportion to glucose content. In such arrangement, the inner membrane was impermeable to glucose and the reaction was monitored by the drop in oxygen. My early membrane polarographic techniques for measurement of hydrogen peroxide were limited to the detection of small molecules which were capable of permeating the membrane for enzymatic reaction with an enzyme being contained on the electrode side of the membrane.
More recently, enzymatic techniques for measuring macromolecules, such as cholesterol have been made. Generally, the enzymatic methods combined two enzymes, cholesterol oxidase and cholesterol ester hydrolase, with colorimetric techniques. These colorimetric methods relied on enzymatic conversion of cholesterol or its esters to cholestenone and hydrogen peroxide, and then on the reaction of the hydrogen peroxide with various compounds to produce measurable chromagens and fluorogens. In my U.S. Pat. No. 4,040,908, I described a membrane polarographic anode suitable for measuring macromolecular substances, such as cholesterol, utilizing enzymatic reactions as a means to measure such macromolecular substances.
Additional techniques have been developed for measuring other biological substances in blood. For instance, ethanol is currently measured in blood either directly or by breath sampling, by classical chemical, gas chromatographic and enzyme methods. One of the alcohol enzyme methods, for example, depends upon the polarographic measurement of hydrogen peroxide, while others depend upon the consumption of oxygen. In my more recent U.S. Pat. No. 4,458,686, I disclosed the use of a polarographic electrode as a skin-contact analyzer to transcutaneously measure oxygen for determining blood substances, such as glucose or alcohol as well as measurement of alcohol going through the skin.
One of the most important biological substances is glucose. This is true because glucose plays such a major role in the metabolism of the body in health and disease, particularly diabetes. For instance, most of the scientific evidence to date indicates that it is the high blood and tissue glucose concentration per se, and not too low an insulin level or the presence of abnormal metabolites, such as hydroxybutyric acid and the like, which causes the organ damage in the various forms of diabetes mellitus. This damage may be caused by glycylation of many of the tens of thousands of proteins in the body. Such glycylation is reflected by the glucosehemoglobin AlC level in the blood, a substance commonly measured to give a time-integrated level for blood glucose. Since all enzymes are proteins, the high glucose level probably impairs the catalytic functions in every part of the body. Typical serious damage related to diabetes is blindness, loss of limbs, cardiac and circulatory failure and death.
At present, insulin is administered either by injecting intermittently throughout the day to control blood glucose or, in a very small population of diabetics, by a programmable pump which injects insulin subcutaneously. This results in considerable, potentially dangerous, fluctuation in blood glucose depending upon the severity of the disease. In some forms of diabetes the Beta cells which make insulin are completely destroyed and the person becomes totally insulin dependent for survival.
In view of the above background, it would be desirable to have a device which is capable of continuously sensing glucose in the blood of diabetic patients so that the insulin or glucose can be more effectively administered and regulated. Extensive efforts heretofore have been directed toward developing an implantable glucose sensor having the capability of controlling an insulin pump or at least to provide a continuous signal reflecting blood glucose concentrations. However, it is widely believed that an implanted enzyme-based glucose sensor cannot work or, if it does work, such a sensor would last at best for only a few days, after implantation in the blood or a body cavity. In Schichiri, M. et al: Glycaemic Control in Pancreatectomized Dogs with a Wearable Artificial Endocrine Pancreas, Diabetologia. 24:179-184 (1983), it was reported that a glucose sensor was implanted and it lasted for six days after the date of in vivo implantation. Up to this point, such success even though limited has been considered remarkable. Nevertheless, the limited operability of such sensors lead the scientific community to believe that implanted glucose oxidase type glucose sensors are not practical. In support of such belief, a penumbra of reasons are given. For instance, it is generally thought that the enzyme, glucose oxidase, is too unstable to remain active for any period of time in a human at human body temperature. Furthermore, it is believed that glucose oxidase would be destroyed by bacteria or fungi. It is further believed that the electrodes' permeable membrane would be destroyed by tissue cells and enzymes or would become plugged as a result of large molecules, cellular debris and white and red blood cells collecting thereon. Additionally, it is thought that the amount of oxygen available necessary for the enzymatic reaction would be insufficient; or that co-enzymes would diffuse away from the enzyme through glucose permeable membranes; or that the platinum electrode surface would become plated, poisoned, inactivated or passivated thereby preventing reduction of the hydrogen peroxide generated; or that tissue response would interfere with glucose permeation through the membrane.
In summary, while there are a variety of devices and techniques available for the measurement of biological substances, new implantable devices and methods are needed for the measurement, administration and/or regulation of key biological substances, such as blood glucose and insulin. It would be especially beneficial if a satisfactory implantable device could be provided to aid in the control and alleviation of diabetes.